The interaction between tumor cells and surrounding non-malignant stromal and immune cells provides a supportive environment for tumor development, growth, invasion, and metastasis. Development of a tumor induces cellular and molecular changes to suppress anti-tumor immune responses mediated by immune effector cells. Myeloid derived suppressor cells (MDSCs) are immature myeloid progenitor cells with potent immune suppressive activities. Increased numbers of MDSCs have been found in many pathologic conditions including infections, inflammatory diseases, and cancer, and correlate with disease prognosis and clinical stage 1. MDSCs directly suppress effector T, NKT, and NK cell-mediated anti-tumor immune responses by producing arginases (ARGs), reactive species of oxygen (ROS), inducible nitric oxide synthase (iNOS), and immunosuppressive cytokines, and by depleting metabolic factors from the microenvironment required for effector cell activation (Youn et al., “The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity.” Eur. J. Immunol. (2011) 40:2969-2975). In mice, MDSCs have been identified with low expression of MHC class II and CD80 (Movahedi et al., “Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity.” Blood (2008) 111:4233-4244; Sawanobori et al., “Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice.” Blood (2008) 111:5457-5466), to be either neutrophil like CD11b+Gr1high (G-MDSC) or monocyte like CD11b+Gr1low cells (M-MDSC) (Movahedi et al., “Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity.” Blood (2008) 111:4233-4244; Kusmartsev et al., “Immature myeloid cells and cancer-associated immune suppression.” Cancer Immunol. Immunother. (2002) 51:293-298; Bronte et al., “Identification of a CD11b(+)/Gr-1(+)/CD31(+) myeloid progenitor capable of activating or suppressing CD8(+) T cells.” Blood (2000) 96:3838-3846; Kusmartsev et al., “Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species.” J. Immunol. (2004) 172:989-999). However, MDSCs in human are characterized by expression of additional phenotypic surface antigens including with high CD11b, CD33, and IL-4Rα expression, low or no CD14 and Lin expression, and variable expression of CD15 (Almand et al., “Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer.” J. Immunol. (2001) 166:678-689; Diaz-Montero et al., “Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy.” Cancer Immunol. Immunother. (2009) 58:49-59). In cancer, MDSCs are tumor supporting, immune suppressive cells and mostly accumulate with a granulocytic-MDSC (G-MDSC) phenotype (Youn et al., “Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice.” J. Leukoc. Biol. (2012) 91:167-181). Alternatively, MDSC-mediated immune suppression plays an important role in autoimmunity, inflammation, and transplantation. MDSC-mediated immune suppression is a major cause for failures in anti-tumor immunotherapy, and therefore, modulation and/or elimination of MDSCs and/or MDSC-mediated immune suppression (e.g., by inhibiting HDACs) is needed for the development of novel anti-tumor therapies.
Proliferation of solid tumors (e.g., breast, lung, ovarian, and prostate cancer) can be modulated by growth factor receptor expression or activity. For example, proliferation of breast cancer cells is mediated by transmembrane growth factor receptors and intracellular hormone/steroid receptors such as epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), estrogen receptor (ER), and progesterone receptor (PGR). Therefore, inhibition of these receptors is a promising therapeutic strategy in the treatment of solid tumors. Indeed, small molecule inhibitors and monoclonal antibodies against these receptors have already been generated and show remarkable clinical outcome. Importantly, simultaneous inhibition of these receptors may be able to enhance activity of individual agents.